Developing Nanopieces, a Platform RNAi Delivery Technology for Treatment of Multiple Diseases

开发 Nanopieces，一种用于治疗多种疾病的 RNAi 传递技术平台

• 批准号: 9777769
• 负责人: QIAN CHEN
• 金额: $ 32.5万
• 依托单位: NANODE THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-21 至 2023-02-20
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9777769
• 关键词: ADAMTS; Affect; Affinity; Amines; Animal Model; Base Pairing; Biomimetics; Cartilage; Cartilage Matrix; Cells; Charge; Chondrocytes; Chondrogenic Neoplasm; Chondrosarcoma; Clinical Data; DNA; Data; Degenerative polyarthritis; Development; Dimensions; Disease; Drug Delivery Systems; Encapsulated; Endocytosis; Extracellular Matrix; FDA approved; Gene Expression; Generations; Genes; Goals; Half-Life; Health; Histology; Hospitals; Human; In Vitro; Joints; Laboratories; Liver; Lysine; Mission; Nanotubes; Nucleic Acids; Outcome; Penetration; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Process; Public Health; RNA Interference; RNA Interference Therapy; RNA delivery; Research; Rheumatoid Arthritis; Rhode Island; Small Business Technology Transfer Research; Small Interfering RNA; Solid Neoplasm; Surface; Technology; Testing; Therapeutic; Therapeutic Effect; Time; Tissues; Toxic effect; Transfection; Translating; United States National Institutes of Health; Universities; base; biomaterial compatibility; commercial application; density; disability; in vivo; innovation; knock-down; nanomaterials; novel; novel therapeutic intervention; nucleic acid delivery; pre-clinical; response; siRNA delivery; small molecule; therapeutic siRNA; therapy outcome

STTR_Developing Nanopieces 7. Project Summary/Abstract The bottleneck of developing new RNAi (RNA Interference) drugs is the lack of highly efficient and non-toxic RNA delivery to non-liver tissues in vivo. It is especially challenging to deliver negatively-charged nucleic acid into avascular, dense, and negatively-charged matrix in hard-to-reach tissues including joint cartilage. NanoDe Therapeutics, Inc. (NanoDe) is a development stage company dedicated to developing delivery of RNAi therapeutics, thereby creating more effective drugs. NanoDe is founded on a novel platform RNA delivery technology termed NanopiecesTM, a novel biomimetic nanomaterial derived from a small molecule JBAK, Janus-Base with Amine or lysine (K). Through self-interaction of its biocompatible Janus-Base units mimicking DNA base pairs, JBAK forms non-covalent nanotubes (NT) with positively charged amine or lysine on the surface. JBAK NT further assembles with siRNA to form JBAK NP, thereby encapsulating negatively charged siRNA into positively charged NP. Our preliminary data has shown that 1) NPs can penetrate matrix-rich tissues that conventional vehicles cannot, and release siRNA therapeutics intracelluarly in high efficiency to modify otherwise untreatable diseases; 2) NP delivered RNAi therapeutics has achieved successful outcomes in the treatment of multiple diseases including rheumatoid arthritis, a rare solid tumor called chondrosarcoma, and post-traumatic osteoarthritis (PTOA) in animal models respectively; and 3) NP has excellent biocompatibility and biodegradability, which are critical for maintaining minimal toxicity in vivo. The goal of this Phase I application is to further develop NP delivery technology by using PTOA as a “use case” disease. The central hypothesis is that the optimal positive charge of NP is one of the critical parameters to enable its penetration into negatively charged cartilage matrix, endocytosis into chondrocytes, and release siRNA to inhibit disease gene expression, thereby achieving significant therapeutic effects on PTOA. This hypothesis will be tested with the two aims: 1) Determining the optimal charge of NP to enable its penetration and retention within cartilage tissue, transfection into chondrocytes, and inhibiting matrix proteinase ADAMTS-5 gene expression in chondrocytes, respectively; and 2) Determining the optimal charge of NP to enable its intra- articular delivery and long half-life within joint, and achieve significant therapeutic outcomes in a PTOA animal model. The proposed research is innovative because: 1) Essentially different from conventional delivery vehicles, Nanopiece is a non-covalent vehicle presenting unique advantages, such as versatility in dimensions and surface charge, affinity to extracellular matrix, excellent biodegradability and biocompatibility. 2) For the first time, we identify important technology parameters of NP required for successful siRNA delivery including the optimal vehicle surface charge for matrix penetration, cell transfection, and gene knockdown. 3) The technology breakthrough enlightens a therapeutic approach to deliver RNAi for treatment of multiple diseases including PTOA.

sttr_develoving Nanopieces 7。项目摘要/摘要 开发新RNAi（RNA干扰）药物的瓶颈缺乏高效且无毒 RNA在体内递送至非肝组织。交付负电荷的核酸尤其具有挑战性 在包括关节软骨在内的难以到达的组织中进入血管，密集和负电荷的基质。纳米 Therapeutics，Inc。（Nanode）是一家致力于开发RNAi交付的开发阶段公司 治疗药，从而产生更多有效的药物。纳米建立在新的平台RNA传递上 技术称为Nanopiecestm，这是一种新型的仿生纳米材料，该纳米材料源自小分子JBAK， Janus-Base与胺或赖氨酸（K）。通过自我交往的生物相容性Janus-base单位模仿 DNA碱基对，JBAK形成非共价纳米管（NT），带正电荷的胺或赖氨酸在 表面。 jbak nt进一步与siRNA组成，形成JBAK NP，从而封装了负电荷的 siRNA成正动的NP。我们的初步数据表明，1）NP可以穿透矩阵富含矩阵 传统车辆无法的组织，并在高效率上细胞内释放siRNA治疗 修改原本不可治疗的疾病； 2）NP交付的RNAi治疗疗法已取得成功的结果 在治疗包括类风湿关节炎在内的多种疾病时，一种称为软骨肉瘤的罕见的实体瘤， 和动物模型中的创伤后骨关节炎（PTOA）； 3）NP很好 生物相容性和生物降解性，这对于维持体内最小毒性至关重要。目标的目标 第一阶段的应用是通过使用PTOA作为“用例”疾病进一步开发NP输送技术。这 中心假设是NP的最佳正电荷是使其能够使其能够的关键参数之一 渗透成负电荷的软骨基质，内吞作用到软骨细胞中，然后释放siRNA 抑制疾病基因表达，从而对PTOA产生显着的治疗作用。这个假设将会 通过两个目的进行测试：1）确定NP的最佳电荷以实现其渗透和保留率 在软骨组织中，转染到软骨细胞中，并抑制基质蛋白酶ADAMTS-5基因 在软骨细胞中的表达； 2）确定NP的最佳电荷以实现其内部 关节递送和长时间寿命内的关节内，并在PTOA动物中获得明显的治疗结果 模型。拟议的研究具有创新性，因为：1）与常规交付基本不同 车辆，纳米制品是一种非共价车辆，具有独特的优势，例如在维度上的多功能性 和表面电荷，对细胞外基质的亲和力，出色的生物降解性和生物相容性。 2） 第一次，我们确定成功交付成功所需的NP的重要技术参数，包括 用于基质渗透，细胞转染和基因敲低的最佳车辆表面电荷。 3） 技术突破启发了一种治疗方法，用于治疗多种疾病 包括PTOA。